Product and method for treating diarrhea

ABSTRACT

A method of treating diarrhea in a patient includes administering an H1 receptor antagonist and an H2 receptor antagonist to the patient.

CROSS-REFERENCE TO RELATED APPLICATION

The present application claims the benefit of U.S. ProvisionalApplication No. 61/782,608 filed 14 Mar. 2013, entitled “PRODUCT ANDMETHOD FOR TREATING DIARRHEA” the entire contents of which are herebyincorporated by reference, except where inconsistent with the presentapplication.

BACKGROUND

Diarrhea is a common condition characterized by increased frequency orfluidity of bowel movements. Diarrhea may cause dehydration andelectrolyte abnormalities that may require hospitalization to replacelost fluids and electrolytes until the symptoms subside. Persistent,uncontrolled diarrhea can cause such severe malnutrition, electrolyteimbalances and dehydration that it may ultimately result in death. Acutediarrhea is usually treated with fluid and electrolyte replacement,dietary modifications and antidiarrheal or antimicrobial agents. Acutediarrhea complications may cause severe illness, especially in high-riskgroups, for example patients with underlying immunosuppression oradvanced age. Antidiarrheal treatment is also required in patients withchronic diarrhea. Empiric therapies routinely used for chronic diarrheainclude: stool-modifying agents (such as psyllium and fiber),anticholinergic agents, opiates, antibiotics, and probiotics.

Chronic diarrhea may be a symptom of a chronic disease, for exampleirritable bowel syndrome (IBS). It has been estimated that theprevalence of chronic diarrhea in the United States is approximately 5%.IBS alone is estimated to affect 15-20% of the U.S. population, andaccounts for at least 30% of all gastroenterology health care costs. Inmany cases, the cause of the chronic diarrhea is not found, thediagnosis remains uncertain, and empiric treatments unsuccessful. Thus,there is an ongoing need for antidiarrheal agents that effectively stopor greatly reduce bowel movements and fluid loss in patients undergoingtreatment, to remove the cause of diarrhea, or in patients in which thecause of diarrhea is not found.

H1 and H2 receptor antagonists are two classes of antihistamines. H1receptor antagonists are used in the symptomatic treatment of multipleconditions, including allergic rhinoconjunctivitis, relief of pruritusin patients with urticaria, and in patients with chronic asthma. NewerH1 receptor antagonists, such as cetirizine, are referred to assecond-generation H1 receptor antagonists, and are more selective forperipheral H1 receptors than first-generation H1 receptor antagonist,which antagonize both the central and peripheral nervous system H1receptors as well as cholinergic receptors. The selectivitysignificantly reduces the occurrence of adverse drug reactions, such assedation, while still providing effective relief of allergic conditions.

H2 receptor antagonists are used primarily to treat symptoms of acidreflux, or gastroesophageal reflux disease. H2 receptor antagonistsreduce the production of stomach acid. Often diarrhea is listed as amajor side effect of H2 receptor antagonists.

Diphenhydramine, a first-generation H1 receptor antagonist, togetherwith either cimetidine or ranitidine, H2 receptor antagonists, have beenstudied for the treatment of acute allergic reactions. In a first study(Runge et al. “Histamine antagonists in the treatment of acute allergicreactions” Ann Emerg Med (March 1992) 21:237-242), patients were treatedby a single intravenous administration of a solution 300 mg cimetidineand placebo, 50 mg diphenhydramine and placebo, or diphenhydramine pluscimetidine; the treatment was found effective for acute urticaria. In asecond study (Lin et al. “Improved outcomes in patients with acuteallergic syndromes who are treated with combined H1 and H2 antagonists”Ann Emerg Med (November 2000) 36:462-468), patients were treated by asingle parenteral administration of a solution of either 50 mgdiphenhydramine and saline or 50 mg diphenhydramine and 50 mgranitidine; the treatment was found effective for acute allergicsyndromes.

SUMMARY

In a first aspect, the present invention is a method of treatingdiarrhea in a patient, comprising administering an H1 receptorantagonist and an H2 receptor antagonist to the patient. Preferably, theH1 receptor antagonist comprises cetirizine and the H2 receptorantagonist comprises famotidine.

In a second aspect, the present invention is a method of treatingdiarrhea in a patient, comprising administering an H1 receptorantagonist and an H2 receptor antagonist to the patient. Preferably, theH2 receptor antagonist is not ranitidine.

In a third aspect, the present invention is a method of treatingdiarrhea in a patient, comprising administering an H1 receptorantagonist and an H2 receptor antagonist to the patient.

In a fourth aspect, the present invention is a method of treatingdiarrhea in a patient, comprising administering an H1 receptorantagonist and an H2 receptor antagonist to the patient. Preferably, thepatient does not have mastocytic enterocolitis.

In a fifth aspect, the present invention is a pharmaceutical compositionfor treating diarrhea, comprising an H1 receptor antagonist, and an H2receptor antagonist. Preferably, the H2 receptor antagonist is notranitidine, and the pharmaceutical composition is an oral dosage form.

In a sixth aspect, the present invention is a pharmaceutical compositionfor treating diarrhea, comprising an H1 receptor antagonist, and an H2receptor antagonist. Preferably, the H1 receptor antagonist is notdiphenhydramine.

In a seventh aspect, the present invention is a pharmaceuticalcomposition for treating diarrhea in a patient, comprising an H1receptor antagonist, and an H2 receptor antagonist. Preferably, thepatient does not have mastocytic enterocolitis.

In an eighth aspect, the present invention is use of an H1 receptorantagonist and an H2 receptor antagonist for the preparation of amedicament for treating a patient having diarrhea.

DEFINITIONS

The term “diarrhea,” means increased fluidity or frequency of stools.

The term “acute diarrhea” is ongoing diarrhea which has occurred for atmost 4 weeks.

The term “chronic diarrhea” is ongoing diarrhea for more than 4 weeks.

The term “unit dosage form,” means a single pre-measured dose, andincludes tablets, pills, capsules, packets, suspensions, transdermalpatches, and rectal suppositories.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates participants and responses by treatment group of anIBS-D study.

DETAILED DESCRIPTION

The present invention makes use of the discovery that administering anH1 receptor antagonist and an H2 receptor antagonist to a patient,results in a significant reduction or cessation of diarrhea. Applicantdiscovered that the combination of an H1 receptor antagonist and an H2receptor antagonist administered to patients with diarrhea, resulted in85-90% positive responders (see Example 7 and Table 1). A positiveresponder is identified as having a 50% or more reduction in the numberof stools per day or a change in stool formation from liquid to solid.No adverse reactions or events were reported. A control group wastreated with fiber (Metamucyl®) and an anticholinergic (Bentyl®);positive responders in the control group were less than 25%.

In a prior study (Jakate, et al., “Mastocytic Enterocolitis: Increasedmucosal mast cells in chronic intractable diarrhea” Arch Pathol Lab Med(2006) 130:362-367), 33 patients who had increased mast cells (greaterthan 20 mast cells per high-power field) and were therefore identifiedby the authors as having “mastocytic enterocolitis,” were administered a2-week regimen of 10 mg per day of cetirizine hydrochloride (an H1receptor antagonist) and 300 mg twice a day of ranitidine hydrochloride(an H2 receptor antagonist). In 8 of the 33 patients, a third drug, 200mg/10 mL of cromolyn sodium (a mast cell mediator release inhibitor) wasgiven 4 times daily for 4 to 6 weeks. The patients were followed forresolution, improvement, or persistence of symptoms. The patients whodid not have mastocytic enterocolitis were not given these drugs. Atfollow-up, 22 (67%) of the 33 study patients showed cessation ofdiarrhea or significant reduction in diarrhea (defined as greater thanor equal to 50% reduction in stool frequency or as greater than or equalto 50% improvement in stool consistency). However, because no controlwas used in the study, and because of the use of a third drug in some ofthe patients, it is not possible to determine how effective thetreatment was for the selected patients. The placebo effect couldaccount for up to about 11 of the patients with a positive outcome andthe third drug could account for up to 8 of the patients with a positiveoutcome. The time frame of the follow-up was not provided. Furthermore,no statistical analysis or further studies were described.

The present invention includes treating diarrhea by administering an H1receptor antagonist and an H2 receptor antagonist in combination. Thepresent invention also includes unit dosage forms, multi-dosage forms,and kits, including an H1 receptor antagonist and an H2 receptorantagonist. Preferably, the H1 receptor antagonist includes cetirizineand the H2 receptor antagonist includes famotidine.

Diarrhea may be acute or chronic. Diarrhea may also be furtherclassified:

-   -   Secretory diarrhea: diarrhea which occurs when the intestine        does not complete absorption of water from luminal contents and        electrolyte absorption is impaired, often caused by bacterial        toxins, surgically reduced absorptive area of the intestines,        microscopic colitis and luminal secretagogues such as laxatives        and bile acids.    -   Osmotic diarrhea: diarrhea which results from intestinal        malabsorption of ingested non-electrolytes.    -   Inflammatory diarrhea: diarrhea which may be characterized by        blood and pus in the stool and possibly an elevated fecal        calprotectin level, and inflammation exhibited on intestinal        biopsy, caused by, for example, Crohn's disease and ulcerative        colitis.    -   IBS-diarrhea predominate (“IBS-D”): chronic diarrhea associated        with abdominal pain. In order to have IBS, a patient must have        experienced onset of symptoms 6 months prior to diagnosis and        must have recurrent abdominal pain or discomfort at least three        days per month in the last three months associated with two or        more of the following: improvement with defecation; onset        associated with a change in frequency of stool; onset associated        with a change in form of stool. Once IBS is diagnosed, it can be        further classified based on the patients predominant symptom:        diarrhea (IBS-D), or constipation (IBS-C), or mixed (IBS-M).    -   Functional diarrhea: chronic diarrhea in a patient who does not        meet the criteria for IBS, and for which no other cause can be        determined. This type of diarrhea may also be referred to as        chronic idiopathic diarrhea.    -   Malabsorbtive diarrhea: diarrhea caused by an enteropathy such        as celiac disease (celiac sprue) and giardiasis, which is        characterized by excess gas, steatorrhea, and/or weight loss.    -   Drug induced diarrhea: diarrhea caused by a drug or treatment        for an unrelated disease state, such as chemotherapy, radiation        therapy, antibiotic therapy, anti-ulcer therapy, and herbal        therapies.    -   Food intolerance diarrhea: diarrhea which is associated with        dietary intake, such as lactose, sugar substitutes or other food        substances.

Particularly common is IBS associated diarrhea, a chronic diarrhea, alsoreferred to IBS-diarrhea predominate or simply “IBS-D”. Some researchersclaimed to have identified a subset of IBS-D, mastocytic enterocolitis,which they defined as a patient having greater than 20 mast cells perhigh-power field, based on an average of 10 high-power fields, for atleast 2 separate biopsy pieces from random parts of the intestinalmucosa, using an original magnification of ×400, an objective havingmagnification of ×40 and an eyepiece having magnification of ×10(Jakate, et al., “Mastocytic Enterocolitis: Increased mucosal mast cellsin chronic intractable diarrhea” Arch Pathol Lab Med (2006)130:362-367). In an aspect of the present invention, the patient doesnot have mastocytic enterocolitis.

H1 receptor antagonists block H1 histamine receptors; first-generationH1 receptor antagonists block histamine receptors in the central andperipheral nervous systems, as well as cholinergic receptors, whilesecond-generation H1 receptor antagonists are selective for H1 histaminereceptors in the peripheral nervous system. First-generation H1 receptorantagonists include brompheniramine, chlorpheniramine,dexbrompheniramine, dexchlorpheniramine, pheniramine, triprolidine,carbinoxamine, clemastine, diphenhydramine, pyrilamine, promethazine,hydroxyzine, azatadine, cyproheptadine, and phenindamine.Second-generation H1 receptor antagonists include ketotifen, rupatadine,mizolastine, acrivastine, ebastine, bilastine, bepotastine, terfenadine,quifenadine, azelastined, cetirizine, levocetirizine, desloratadine,fexofenadine and loratadine. Preferably, the H1 receptor antagonist is asecond-generation H1 receptor antagonist, more preferably the H1receptor antagonist is cetirizine or levocetirizine, with cetirizinebeing particularly preferred. Mixtures and combination of H1 receptorantagonists may also be used.

The H1 receptor antagonists may be used in an amount of from 0.1 to 10times the amount typically used for the treatment of allergies, forexample in an amount of 0.1 to 600 mg per dose, 0.5 to 500 mg per dose,1.0 to 50 or 60 mg per dose, including 1.25, 1.5, 1.75, 2.0, 2.5, 3.0,3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40 and 45 mg per dose.Preferably, the H1 receptor antagonist is administered 1, 2, 3 or 4times per day. The H1 receptor antagonist may be administered as aninjectable formulation, for example intravenously, intraparenterally orintramuscularly; transdermally, via a transdermal patch; or, preferably,orally, as a powder, table or capsule, an oral solution or suspension,or sublingual or buccal tablets. Alternative forms of administrationinclude rectal suppositories, inhaled, epidural, subcutaneous, nasalspray, transmucosal, and intradermal formulations.

H2 receptor antagonists block H2 histamine receptors. H2 receptorantagonists include cimetidine, ranitidine, famotidine, and nizatidine,with famotidine being preferred. Mixtures and combinations of H2receptor antagonists may also be used.

The H2 receptor antagonists may be used in an amount of from 0.1 to 10time the amount typically used for treatment dyspepsia, for example 1.0to 8000 mg per dose, 2.0 to 1000 mg per dose, 5.0 to 800 mg per dose,including 6.0, 7.0, 8.0, 9.0, 10, 15, 20, 21, 22, 22.5, 23, 24, 25, 26,27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100,120, 140, 150, 175, 200, 250, 300, 350, 400, 450, 500, 600, and 700 mgper dose. Preferably, the H2 receptor antagonist is administered 1, 2, 3or 4 times per day. The H2 receptor antagonist may be administered as aninjectable formulation, for example intravenously, intraparenterally orintramuscularly; transdermally, via a transdermal patch; or, preferably,orally, as a powder, table or capsule, an oral solution or suspension,or sublingual or buccal tablets. Alternative forms of administrationinclude rectal suppositories, inhaled, epidural, subcutaneous, nasalspray, transmucosal, and intradermal formulations.

Patients often respond to treatment within 48 to 72 hours. However,treatment should be carried out for an amount of time to resolve anyunderlying cause in the case of acute diarrhea, for example 3 to 14days, or 5 to 10 days. In the case of chronic diarrhea, a 30 day trialis reasonable, and if the underlying cause of the diarrhea cannot beresolved, for example in the case of IBS-D, then treatment should becontinued indefinitely.

Preferably, the H1 and H2 receptor antagonists are administeredsimultaneously, as a unit dosage form containing both receptorantagonists. Examples of unit dosage forms include oral compositions,such as tablets (for example, sublingual or buccal tablets), capsules(for example, hard gelatin and soft gelatin capsules), transmucosal andsublingual patches and films, pre-measured powder packets and saches,flavored and/or sweetened aqueous solutions or suspensions. Becausediarrhea is often associated with dehydration, flavored and/or sweetenedaqueous solutions or suspension may be oral rehydration solutions, orsolutions which also contain sodium and glucose or a glucose-containingsaccharide, in amounts of 250 ml, 500 ml or 1 liter of fluid.Furthermore, a pre-measured powder packet, containing the receptorantagonists, together with sodium (for example, as sodium chloride) andglucose or a glucose-containing saccharide, and optionally otherexcipients, flavorings and/or sweeteners, may be provided, which may bereadily mixed with water prior to consumption. Preferably, the oral unitdosage form is present as a once-per-day dosage.

Examples of oral dosage forms include a tablet containing famotidine, inan amount of 5, 10, 15, 20, 22.5, 25, 30, 35 or 40 mg, as a core, and acoating of cetirizine, in an amount of 2.5, 5, 8.5, 10, 15, or 20 mg.Another example includes a capsule containing granules of famotidine andcetirizine in water-soluble matrix. In another example, both thefamotidine and the cetirizine are present as a mixture in a matrix,either as a table or within a capsule. In these examples, other H1and/or H2 receptor antagonists may be used in place of, or in additionto, famotidine and/or cetirizine.

Other unit dosage forms may also be provided, containing both H1 and H2receptor antagonist. For example, injectable formulation containing asterile solution or suspension, including formulation for administrationintravenously, intraparenterally or intramuscularly, may be provided. Aunit dosage form for administration transdermally, via a transdermalpatch, may be provided. Other unit dosage forms include rectalsuppositories, inhaled, epidural, subcutaneous, nasal spray, andintradermal formulations. Excipients and adjuvants maybe also beincluded in any of the unit dosage forms, both oral and non-oral.

Multi-dosage forms, such as kits, containing 2 to 30, 3 to 25, or 5 to14 unit dosage forms, for example 6, 7, 8, 9, 10, 11, 12, 13, 15, 20,40, 50 or 60 unit dosage forms, may be provided. Preferably, themulti-dosage forms contain sufficient unit dosage forms foradministration over a period of 2 to 30, 3 to 25, or 7 to 14 days, forexample 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 20 or 30 days. Kits may alsobe provided, which include oral rehydration solutions, or powders whichmay be hydrated to form oral rehydration solutions, or kits containingsodium and glucose or a glucose-containing saccharide, as well as otherexcipients, flavorings and/or sweeteners, together with unit dosageforms.

EXAMPLES Example 1 Treatment of Secretory Diarrhea

Patient #1, age 65, was hospitalized for more than one week for weightand fluid loss related to chronic diarrhea. The patient had from 20 to40 stools per day and severe life threatening diarrhea. The patient wastreated with 20 mg famotidine and 10 mg cetirizine, once per day.Symptoms subsided within 48 hours with a 95% decrease in the number ofstools and the patient was discharged. The patient responded totreatment and now has 1 stool per day, occasionally two, but nodiarrhea.

Example 2 Treatment of IBS Diarrhea

Seven patients, age 26 to 80, were treated for mild to severe diarrhea,ranging from 3 to 18 stools per day.

Patient #1, age 80, with mild to severe cramping and 4 to 5 stools aday. The patient was treated with 300 mg ranitidine and 10 mgcetirizine, once per day. The patient reported a 60% reduction in thenumber of stools.

Patient #2, age 62, had severe weight loss, greater than 30 pounds,related to the diarrhea, 10 to 20 stools per day, and was opiate andsteroid dependant. The patient was treated with 20 mg famotidine and 10mg cetirizine, once per day. Treatment was successful with an 85 to 90%reduction in the number of stools. The patient now has 1 to 2 stools perday for over 8 months on treatment.

Patient #3, age 65, prior to treatment was homebound, had 4 to 5 stoolsper day, each episode lasting an hour or two. The patient was treatedwith 300 mg ranitidine and 10 mg cetirizine, once per day. Treatment wassuccessful, with the patient reporting a 90% reduction in the number ofstools.

Patient #4, age 67, with moderate diarrhea and cramping, had 4 to 5stools per day. The patient was treated with 20 mg famotidine and 10 mgcetirizine, once per day. Treatment was successful, with a 75% reductionin the number of stools, no cramping and no side effects.

Patient #5, age 26, had moderate to severe diarrhea with 7 to 8 stoolsper day. The patient was treated with 20 mg famotidine and 10 mgcetirizine, once per day. Treatment was successful, with a decrease inthe number of stools by 50%, down to 3 to 4 per day, with no sideeffects.

Patient #6, age 74, with severe diarrhea, had 8 stools per day and washomebound. The patient was treated with 300 mg ranitidine and 10 mgcetirizine, once per day. Treatment was successful, with a decrease inthe number of stools by 75%, down to 2 stools per day and no sideeffects. Patient is presently only on cetirizine.

Patient #7, age 51, with colon resection, had severe diarrhea with 15 to20 stools per day. The patient was treated with 300 mg ranitidine and 10mg cetirizine, once per day. Treatment was successful, with a decreasein the number of stools by 94%, to 1 to 2 stools per day and betterconsistency, with no side effects.

Example 3 Chronic Idiopathic Diarrhea

A patient, age 81, with a complaint of moderate diarrhea and noadditional diagnoses, had 4 to 6 stools per day, causing interferencewith activity level and lifestyle. The patient was treated with 20 mgfamotidine and 10 mg cetirizine, once per day. Treatment was successful,with a decrease in the number of stools by 70%, to 1 to 2, mostly 1, perday and a repeat colonoscopy was cancelled because symptoms hadresolved.

Example 4 Chemotherapy Induced Diarrhea

Patient, age 64, with colon cancer and moderate to severe diarrhea, in adeconditioned state from chemotherapeutic agents, had 5 to 10 stools perday. The patient was treated with 20 mg famotidine and 10 mg cetirizine,once per day. Treatment was successful, with a decrease in the number ofstools by 80%, to 1 to 2 per day and normal consistency, with no sideeffects.

Example 5 Inflammatory Diarrhea—Ulcerative Colitis/Crohn's Disease

Three patients, age 35-64, were treated for severe diarrhea related toulcerative colitis or Crohn's disease.

Patient #1, age 64, with Crohn's disease, had 12 to 15 stools per dayand severe diarrhea. The patient was treated with 20 mg famotidine and10 mg cetirizine, once per day. Treatment was not successful, with adecrease in the number of stools only by 5%. There were no side effects.

Patient #2, age 37, with Crohn's disease and colitis, had severediarrhea with 4 to 5 stools per day. The patient was treated with 300 mgranitidine and 10 mg cetirizine, once per day. Treatment was successful,with a decrease in the number of stools by 75%, to one stool per day andnormal consistency. There were no side effects.

Patient #3, age 35, with ulcerative colitis, had severe diarrhea with 4to 6 stools per day. The patient was treated with 20 mg famotidine and10 mg cetirizine, once per day. Treatment was successful, with adecrease in the number of stools by 50%. There were no side effects.

Example 6 Celiac Disease

Patient #1, age 57, with celiac disease had mild to moderate diarrhea,with 2 to 4 stools per day. The patient had no improvement fromtreatment with 20 mg famotidine and 10 mg cetirizine, once per day.There were no side effects.

Patient #2, age 26, with celiac disease. The patient had littleimprovement from treatment.

Example 7 IBS-D Treatment Study

The study population age was 18 to 80, with the patients having chronicunexplained diarrhea from an outpatient population of a clinic andoutpatients from a medical center, who gave consent for treatment.Patients were excluded who had a history of systemic or cutaneousmastocytosis, definable etiology of diarrhea (other than IBS-D orchronic idiopathic diarrhea) such as celiac disease, inflammatory boweldisease, or lactose intolerance, or who were pregnant. The study wasinitiated after IRB approval.

Upon referral to the study coordinator, and after informed consent wasobtained, patients were assigned to one of the two study arms. Patientsunderwent colonoscopy with biopsies that were then evaluated by apathologist who was blind to the study arm. The study coordinatorreviewed pathology results and documents accordingly. The patient wasprovided the treatment method that was randomly assigned and given adiary to document symptoms. Follow up phone conversations and a returnvisit was scheduled. At the completion of the four week medicationtreatment period, a telephone call or visit was carried out. At eightweeks, the diary was returned and the coordinator documented the datarecorded by the subjects. There was a process for adverse eventreporting and to date, no adverse reactions or events have beenreported.

One study arm received famotidine (20 mg per day) and cetirizine (10 mgper day), once per day. The second study arm received fiber (Metamucil®)and an anticholinergic (Bentyl®) once per day. Table 1 shows the resultsof the study. Tables 2 and 3 show the statistical analysis of the studyresults.

TABLE 1 Study results Treatment Number of Positive Non- Percent GroupParticipants Responders Responders Responding famotidine and 26 25 1 96%cetirizine dicylcomine 8 2 6 25% and psyllium Positive responders =Appreciable decrease in # of stools per day Non-responders = Noappreciable decrease in # of stools per day

TABLE 2 Group statistics Treatment Std. Error Group N Mean Std.Deviation Mean dicylcomine 8 0.13 0.354 0.125 and psyllium famotidineand 26 1.00 0.000 0.000 cetirizine

TABLE 3 Independent samples test Independent Samples Test t-test forEquality of Means Levene's Test 95% Confidence for Equality of Intervalof the Variances Sig. (2- Mean Std. Error Difference Status F Sig. t dftailed) Difference Difference Lower Upper Equal 19.033 0.000 −13.088 320.000 −8.75 0.67 −1.011 −.739 variances assumed Equal 19.033 0.000−7.000 7.000 0.000 −8.75 0.125 −1.171 −.579 variances not assumed

FIG. 1 illustrates participants and responses by treatment group. Thebars on the left represent the patients who received famotidine andcetirizine, while the bars on the right represent the patients whoreceived fiber and anticholinergic. As indicated in the table and thefigure, 90% of the patients receiving famotidine and cetirizineresponded to the treatment, while only 10% of those receiving fiber andanticholinergic responded to the treatment.

Tables 4 and 5 show the percent decrease in number of stools per day,for the famotidine and cetirizine study arm, and the dicylcomine andpsyllium study arm, respectively.

TABLE 4 Percent decrease in number of stools per day, for the famotidineand cetirizine study arm Number of Subjects Percent Stool Decrease 1 0%1 10-25% 2 28-45% 11 50-65% 11 66-85% 0 >86% 

TABLE 5 Percent decrease in number of stools per day, for thedicylcomine and psyllium study arm Number of Subjects Percent StoolDecrease 6 0% 0 10-25% 1 28-45% 1 50-65% 0 66-85% 0 >86% 

Example 8 Chronic Diarrhea Treatment Study

The study population age was 21 to 70, with patients diagnosed withchronic diarrhea, who gave consent for treatment. Patients were excludedif there was a sensitivity or allergy to H1 receptor antagonists or H2receptor antagonists, renal impairment or a history of renal failure, adiagnosis of inflammatory bowel disease (Crohn's disease or ulcerativecolitis), a known active infection of the colon (such as Clostridiumdifficile, giardia, or Salmonella), biopsy proven microscopic colitis(collagenous or lymphocytic colitis), or an inability to discontinueother anti-diarrheal agents during the study. Patients were alsoexcluded if they were pregnant or lactating women, or if the patient wastaking atazanavir, itraconazole, or ketoconazole. The study wasinitiated after IRB approval.

The study was a 4-week randomized, double-blind, controlled trial, withcrossover. After informed consent was obtained, patients were randomlyassigned to one of the two groups (active or placebo), with neither thepatients nor the physicians knowing to which group each patient wasassigned. Each patient was provided the treatment method that wasrandomly assigned and given a diary to document symptoms. After 7 daysof treatment, subjects participated in a telephone interview with ablinded member of the research team. Crossover was allowed after oneweek of treatment for non-responders. At the end of the 28 day study,the patients completed a detailed questionnaire. Stool quality wasevaluated using the 7 point Bristol Stool Scale.

The “active” group received famotidine (24 mg) and cetirizine (9 mg),once per day, with both drugs combined in the form of a single capsule.The “placebo” group received a capsule once per day, which contained noactive ingredients.

The results of the study are shown in Table 6. The table shows theresults of 27 patients, 12 in the placebo group and 15 in the activegroup. The average value for percent change is stools per day (SPD) was25.08 for the placebo group, while the average value for percent changein SPD was 46.00 for the active group. Only 3 of the active grouppatients agreed to crossover, while 9 of the placebo group patientsagreed to crossover. The data demonstrate a clinical significancebetween the placebo group and the active group, and demonstrate asignificant improvement in the quality of life of the patients in theactive group.

TABLE 6 Results of Chronic Diarrhea Treatment Study Group Number ofPatients Mean Δ% SPD Placebo 12 25.08 Active 15 46.00

REFERENCES

Schiller L R, “Secretory Diarrhea” Current Gastroenterology Reports(1999) 1:389-397.

Schiller, L R, Hogan R B, Morawski, S G, Santa Ana, Calif., Bern M J,Nogaard, R P, Bo-Linn, G W, Fordtran J S, “Studies of the Prevalence andSignificance of Radiolabeled Rice Acid Malabsorption in a Group ofPatients with Idiopathic Chronic Diarrhea” Gastroenterology (1997)92:151-160.

Fordtran J S, Santa Ana Calif., Morawski S G, et al. “Pathophysiology ofchronic diarrhea: insights derived from intestinal perfusion studies in31 patients” Gastroenterol Clin North Am (1986) 15:477-490.

Lunardi C, Bambara L M, Biasi D, et al. “Double-blind cross-over trialof oral sodium cromoglycate in patients with irritable bowel syndromedue to food intolerance” Clin Exp Allergy (1991) 21: 569-572.

Fine K D, Schiller U R, “AGA technical review on the evaluation andmanagement of chronic diarrhea” Gastroenterology (1999) 116:1464-1486.

O'Sullivan et al. “Increased mast cells in the irritable bowel syndrome”Neurogastroenterol. Mot. (2000) 12:449-457.

Spiller R C, Jenkins D, Thornley J P, Hebden J M, Wright T, Skinner M,Neal K R, “Increased rectal mucosal enteroendocrine cells, Tlymphocytes, and increased gut permeability following acuteCampylobacter enteritis and in post-dysenteric irritable bowel syndrome”Gut (December 2000) 47(6):804-11.

Theoharides T C Cochrane D E, “Critical role of Mast Cells ininflammatory diseases and the effect of acute stress” J Neuroimmunol(2004) 146:1-12.

Barbars G, De Giorgio et al. “New pathophysiological mechanisms inirritable bowel syndrome” Aliment Pharmacol Ther (2004) 20(suppl.2):1-9.

Dunlop S P, Hebden et al. “Abnormal intestinal permeability in subgroupsof diarrhea-predominant irritable bowel syndromes” Am J Gastroenterol(2006) 101(6):1288-1294.

Barbara G, Stanghellini V et al. “Functional gastrointestinsl disordersand mast cells: implications for therapy” Neurogastroenterol Motil(2006) 18:6-17.

Halvorson H A et al. “Postinfectious irritable bowel syndrome-ameta-analysis” Am J Gastroenterol (2006) 101:1894-1899.

Posserud I et al. “Small intestinal bacterial overgrowth in patientswith irritable bowel syndrome” Gut (2007) 56:802-808.

Lewis, J, Candelora, J, Hogan, I I, RB, Briggs, F, Abraham, S,“Crystal-Storing Histiocytosis Due to Massive Accumulation ofCharcot-Leyden Crystals: A Unique Association Producing ColonicPolyposis in a 78-year-old Woman With Eosinophilic Colitis” Am J SurgPathol. (March 2007) 321(3):481-485.

Jakate S, et al. “Mastocytic enterocolitis increased mucosal mast cellsin chronic intractable diarrhea” Arch Pathol Lab Med, (2006)130:362-367.

Kirsch R H, Riddell R, “Histopathological alterations in irritable bowelsyndrome” Modem Pathology (2006) 19:1638-1645.

Ramos L, Vicario M, Santos J, “Stress-mast cell axis and regulation ofgut mucosal inflammation: from intestinal health to an irritable bowel”Med Clin (Barc) (June 2007) 129(2):61-69.

Piche T, Saint-Paul M C et al. “Mast cells and cellularity of thecolonic mucosa correlated with fatigue and depression in irritable bowelsyndrome” Gut (2008) 57:468-473.

Visser J, Rozing et al. “Tight Junctions, intestinal permeability andautoimmunity celiac disease and type 1 diabetes paradigms” Ann NY AcadSci (2009) 1165:195-205.

Walker M M, Talley N J, et al. “Duodenal mastocytosis, eosinophilia andintraepithelial lymphocytosis as possible disease merkers in theirritable bowel syndrome and functional dyspepsia” Aliment PharmacolTher (2009) 29:765-773.

Thabane M, Marshall J K, “Post-infectious irritable bowel syndrome”World J Gastroenterol. (2009) 15(29):3591-3596.

Walker M M, Salehian S S et al. “Implications of eosinophilia in thenormal duodenal biopsy—an association with allergy and functionaldyspepsia” Aliment Pharmacol Ther (2010) 31:1229-1236.

Klooker T K, Braak B, Koopman K E et al. “The mast cell stabilizerketotifen decreases visceral hypersensitivity and improves intestinalsymptoms in patients with irritable bowel syndrome” Gut (2010)59:1213-21.

Martinez C, et al. “The Jejunum of Diarrhea-Predominant Irritable BowelSyndrome Shows Molecular Alterations in the Tight Junction SignalingPathway That Are Associated With Mucosal Pathobiology and ClinicalManifestations” Am J Gastroenterol (2012) 107:736-746.

Theoharides T C, Shahrzad A, Chen J, Huizinga J, “Irritable BowelSyndrome and the Elusive Mast Cell” Am J Gastroenterol (2012)107:727-729.

Smith M J, “IBS remains a mysterious disorder with few effectiveRemedies” Gastroenterology and Endoscopy News (April 2012) Vol. 63:4.

Pyleris E, Giamarellos-Bourboulis E J, et al. “The prevalence ofovergrowth by aerobic bacteria in the small intestine by small bowelculture: relationship with irritable bowel syndrome” Dig Dis Sci. (May2012) 57(5):1321-9.

Vivinus-Nebot M, Dainese R, et al. “Combination of allergic factors canworsen diarrheic irritable bowel syndrome: role of barrier defects andmast cells” ACG (2012) 107:74-81

Akhavein A, Patel N R, et al. “Allergic Mastocytic Gastroenteritis andcolitis: and unexplained etiology in chronic abdominal pain andgastrointestinal dysmotility” Gastroenter Research and Practice (2012)2012:950582.

Martinez C, Lobo B, et al. “Diarrhoea-predominant irritable bowelsyndrome: an organic disorder with structural abnormalities in thejejunal epithelial barrier” Gut (2012) [Epub ahead of print: 25 May2012].

Braak B, Klooker T K et al. “Mucosal immune cell numbers and visceralsensitivity in patients with irritable bowel syndrome: is there anyrelationship?” Am J Gastroenterol (2012) 107:715-726.

Theoharides T C, Asadi S, Chen J, Huizinga J D, “Irritable bowelsyndrome and the elusive mast cells” Am J Gastroenterol (2012)107(5):727-729.

Farhadi A, Fields J Z, Keshavarzian A, “Mucosal mast cells are pivotalelements in inflammatory bowel disease that connect the dots: stress,intestinal hyperpermeability and inflammation” World J Gastroenterol(2007) 13(22):3027-3030.

Juckett G, Trivedi R, “Evaluation of chronic diarrhea” American FamilyPhysician [serial online]. Nov. 15, 2011; 84(10):1119-1126.

Diarrhea [electronic resource] National Digestive Diseases InformationClearinghouse. (2011). Bethesda, Md.: U.S. Dept. of Health and HumanServices, National Institutes of Diabetes and Digestive and KidneyDiseases.

Forbes D, O'Loughlin E, Scott R, Gall D, “Laxative abuse and secretorydiarrhoea” Arch Dis Child (1985) 60(1):58-60.

DuPont, H. L. et al., “Diarrhea”, National Digestive DiseasesInformation Clearinghouse, January 2012.

Lever, D. D., et al., “Acute Diarrhea”, Center for Continuing Educationpublications: Disease Management Project, Cleveland Clinic, Aug. 1,2010.

H2 blockers, MedlinePlus®, U.S. National Library of Medicine, NIH,updated: Aug. 11, 2011.

Runge et al. “Histamine antagonists in the treatment of acute allergicreactions” Ann Emerg Med (March 1992) 21:237-242.

Lin et al. “Improved outcomes in patients with acute allergic syndromeswho are treated with combined H1 and H2 antagonists” Ann Emerg Med(November 2000) 36:462-468.

He, Shuang; Li, Feng; Zhou, Dan; Du, Junrong; Huang, Yuan, Drugdevelopment and industrial pharmacy, (October 2012) 38(10)1280-1289.

Akin C, Valent P, Metcalfe D D “Mast cell activation syndrome: Proposeddiagnostic criteria” J Allergy Clin Immunol. (2010) 126(6):1099-104.

Hamilton M J, Hornick J L, Akin C, Castells M C, Greenberger N J “Mastcell activation syndrome: a newly recognized disorder with systemicclinical manifestations” J Allergy Clin Immunol. (2011) 128(1):147-152.

Valent P “Mast cell activation syndromes: definition and classification”Allergy (2013) [Epub ahead of print 15 Feb. 2013].

What is claimed is:
 1. A method of treating diarrhea in a patient,comprising administering an H1 receptor antagonist and an H2 receptorantagonist to the patient, wherein the patient does not have mastocyticenterocolitis, the patient has IBS-D, the H1 receptor antagonist iscetirizine, levocetirizine, or mixtures thereof, and the H2 receptorantagonist is famotidine.
 2. The method of claim 1, wherein the H1receptor antagonist and the H2 receptor antagonist are administeredsimultaneously.
 3. The method of claim 1, wherein the H1 receptorantagonist and the H2 receptor antagonist are administered once per dayfor at least 2 days.
 4. The method of claim 1, wherein the patient haschronic diarrhea.
 5. The method of claim 1, wherein the famotidine isadministered in an amount of 10 to 40 mg.
 6. The method of claim 1,wherein the cetirizine, levocetirizine or mixtures thereof isadministered in an amount of 5 to 20 mg.
 7. The method of claim 1,wherein the H1 receptor antagonist and the H2 receptor antagonist areadministered once per day for at least 7 days.
 8. The method of claim 2,wherein the cetirizine, levocetirizine, or mixtures thereof isadministered in an amount of 5 to 20 mg, and the famotidine isadministered in an amount of 10 to 40 mg.
 9. The method of claim 8,wherein the cetirizine, levocetirizine, or mixtures thereof and thefamotidine are administered together as a unit dosage form.
 10. Themethod of claim 1, wherein the cetirizine, levocetirizine, or mixturesthereof and the famotidine are administered together as a unit dosageform.
 11. A method of treating IBS-D in a patient, comprising:administering an H1 receptor antagonist and an H2 receptor antagonist tothe patient, wherein, the H1 receptor antagonist is cetirizine,levocetirizine, or mixtures thereof, the H2 receptor antagonist isfamotidine, and the patient does not have mastocytic enterocolitis. 12.The method of claim 11, wherein the patient has chronic diarrhea. 13.The method of claim 11, wherein the H1 receptor antagonist and the H2receptor antagonist are administered simultaneously.
 14. The method ofclaim 11, wherein the cetirizine, levocetirizine, or mixtures thereofand the famotidine are administered together as a unit dosage form. 15.The method of claim 13, wherein the cetirizine, levocetirizine, ormixtures thereof is administered in an amount of 5 to 20 mg, and thefamotidine is administered in an amount of 10 to 40 mg.
 16. The methodof claim 11, wherein the famotidine is administered in an amount of 10to 40 mg.
 17. The method of claim 11, wherein the cetirizine,levocetirizine or mixtures thereof is administered in an amount of 5 to20 mg.